Convergent lines of evidence indicate that schizophrenia may involve alterations in glutamate neurotransmission. While human postmortem and animal-model studies have been critical in achieving this understanding, any definitive testing of existing models requires in vivo demonstration in humans of neurotransmitter system pathology. Glutamatergic hypofunction in schizophrenia may be reflected by alterations in brain metabolite levels, as suggested in prior studies. In this exploratory grant request, we aim to create novel methodologies to measure glutamate-related neurochemical profiles in schizophrenia using proton magnetic resonance spectroscopy (MRS) at 7 T, taking advantage of the high field benefits of signal gain and spectral resolution enhancement. We have developed new 7 T MRS methods recently that allow precise measurements of several experimentally-challenging brain metabolites, including glutamate, glutamine, GABA, glycine, N-acetylaspartyl-glutamate, glutathione, and myo-inositol, which were achieved by means of echo time optimization of standard MRS sequences. We will measure the concentrations of these brain metabolites, in addition to other major signals in brain MRS (i.e., N-acetylaspartate, creatine and choline), in anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) in volunteers with schizophrenia (SZ) and normal controls (NC). ACC and DLPFC are the brain regions most critically involved in SZ and thus this study will create a focus coincident with a number of prior studies. We will enroll 40 SZ volunteers (20 on- antipsychotic drugs, SZ-ON, and 20 off-medication, SZ-OFF) and 20 age-matched controls. Each patient will undergo a complete workup with a research diagnosis (SCID) interview, cognitive characterization (MATRIC Battery), and symptom assessment (PANSS). MRS data from the groups will be analyzed for differences, then correlated with patient characteristics. We will test whether any of the MRS group differences are associated with specific phenotypes in schizophrenia. Test-retest MRS scans will be conducted with a 2-week interval on 15 subjects (5 SZ-ON, 5 SZ-OFF, and 5 controls) in order to assess the reproducibility of the MRS data. PUBLIC HEALTH RELEVANCE: The pathophysiology of schizophrenia may be reflected by abnormalities in neurochemical concentrations which reflect the activity of cellular transmission. Recently, we have developed new imaging techniques for precise measurements of experimentally-challenging brain metabolites in vivo. We propose, using these methods, to find biomarkers of molecular pathology in schizophrenia, to define the effect of antipsychotic treatment and to examine the correlation between metabolite levels and phenotypic expression of symptoms. This is an essential step toward establishing this new methodology and, ultimately, to better understanding the pathophysiology of the disorder. Eventually, data on altered levels of neurotransmitters and their metabolites, as long as they can be measured with precision, will provide important pieces of data that can be utilized for development of new treatments in schizophrenia.